Cascade impactor

ABSTRACT

The invention relates to low flow rate cascade impactors for sampling aerosols, notably but not limited to pharmaceutical aerosols. The impactor stages serve as both orifice plate and collecting cup, simplifying collection and analysis. The impactor is designed to operate at flow rates approximating the inspiratory flow rates of young children and infants. Also presented is a method of and apparatus for applying a coating material to the collection surface of the stages after an impactor is assembled for use. The method entails generation of a polydisperse aerosol and sampling into the impactor. The coating substance improves the trapping of particles on the stages. The apparatus and method of application limit the amount of coating material applied and confines it to the regions of particle impact opposite the stage orifices.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/977,070 filed 2 Oct. 2007, and PCT/U.S.08/77769 filed 26 Sep. 2008which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the field of aerosol particle sampling.In particular, the invention relates to cascade impactors for samplingpharmaceutical aerosol preparations at low flow rates.

BACKGROUND OF THE INVENTION

A cascade impactor is an aerosol-sampling device that samples andseparates the aerosol according to the aerodynamic properties of theparticles. The typical cascade impactor has multiple collection stagesarranged in series, with each collection stage having an orifice plateand a separate, removable collection surface positioned below theorifices (FIG. 1). With each successive stage, the total cross-sectionalarea of all of the orifices decreases in order to increase the velocityof the particle-laden air and thus the inertia of the entrainedparticles. The collection stages, or plates, serve as an impactionsurface for the collection of the particles possessing inertia too greatto be carried around the collection surface and onward to the nextstage. Thus, successively smaller particles are collected on successivestages. The sizes of the particles collected on each stage, alsoreferred to as the cut size, are primarily determined by the dimensionsof the orifices above the stage and the volumetric flow rate through theimpactor. Particles larger than the cut size are collected by inertialforces on the collection surface, while smaller ones remain entrained inthe air stream to be collected on subsequent stages or a finalcollection filter. The cut size for a stage is the point of 50%collection efficiency.

Cascade impactors have been used in the pharmaceutical industry for manyyears (Hickey, A J. “Methods of Aerosol Particle Size Characterization”Chapter 8 in Hickey, A J ed. Pharmaceutical Inhalation AerosolTechnology, Marcel Dekker, NY 1992 pp. 219-253). The theory of operationis also known in the art (Marple, V A and Rubow, K L “Theory andGuidelines” Chapter 4 in Lodge, J P and Chan, T L eds. Cascade Impactor,Amer Indust Hygiene Assoc 1986 pp. 79-101). The pharmaceutical industryhas long adapted cascade impactors designed for use in industrial andenvironmental sampling to characterize inhalers and devices forrespiratory drug delivery (USP <601> Aerosols). These acceptedpharmaceutical sampling devices are large in size and are typicallyoperated at flow rates ranging from 28 to 100 liters per minute. Atthese high flow rates, numerous orifices must be used on each stage,resulting in operating conditions outside of the ideal range, andconsequently non-ideal calibrations. Further, these devices have largecollection surfaces requiring the collection of relatively large amountsof material to satisfy analytical method requirements. Their size alsocreates inaccuracies in measurement due to interstage losses of materialunaccounted for in routine analysis (Marple V A, Willeke K. Inertialimpactors: theory, design, and use. In: Fine Particles, AerosolGeneration, Measurement, Sampling, and Analysis. Liu BYH ed. AcademicPress, NY, 1975). Further, these devices are not well suited forsampling aerosols intended for delivery to infants and children. Typicalinhalation flow rates for children younger than 15 years of age rangefrom 2 to 4 liters per minute (Coates, A. L., Tipples, G., Leung, K.,Gray, M., Louca, E.; How Many Infective Viral Particles are Necessaryfor Successful Mass Measles Immunization by Aerosol; Vaccine; 24 (2006)1578-1585). Infants, in particular, cannot be instructed to inhale at arapid rate from an inhaler, and so must inhale at their normal tidalrate. Characterization of the dose and particle-size distribution frominhalation delivery devices operating at these low flow rates requiressamplers, and in particular cascade impactors, operating at comparableflows.

Coating of Collection Surfaces with Adhesive Substances

To sample particles other than liquid droplets with a cascade impactor,it is generally accepted that a coating material must be placed on thecollection stage. If not, the particles can bounce or be blown off or bere-entrained by the airflow, thus rendering the analysis of particlesize erroneous. Typically the collection stages are coated by some meansprior to sampling with a greasy, oily, or sticky substance, or a filterpaper. Typically, the entire collection plate is coated by eitherdipping or spray or eyedropper application, and this can result inadditional error for both gravimetric and quantitative chemicalanalysis, due to extraneous materials on the plate. Provided herein areembodiments of apparatuses and methods to apply coating material to onlythe small region opposite the orifices where the particles will impact,thus greatly reducing the quantity of extraneous materials required.

SUMMARY OF THE INVENTION

Compact, low flow rate impactors from which small quantities ofpharmaceutical or other agents can be easily recovered are set forth inembodiments of the invention described herein.

Additional advantages of some embodiments of the invention include areduced number of orifices compared to other cascade impactors, thuseliminating the inaccuracies due to many small holes. Another advantageof some embodiments includes the use of relatively large orificediameters compared to currently available cascade impactors. The largerorifices allow for much easier removal of the particulate matter thatmay be lost in and around the orifices for analysis.

In certain embodiments, the invention comprises a cascade impactor withone or more concentrically nested stages.

In certain embodiments, the invention comprises concentric assembly ofone or more impactor stages slidably coupled together to form a cascadeimpactor.

In certain embodiments of the invention, each impactor stage comprises acylindrical cup further comprising an orifice-containing region and aparticle collecting region.

In certain embodiments, the invention comprises one or more impactorstages wherein the orifices are located on the side walls of the stages.

In certain embodiments, the invention comprises one or more impactorstages wherein the collection surfaces are located on the side walls ofthe stages.

In certain embodiments, the invention comprises one or more impactorstages wherein the orifices are on the bottom surface of the stages.

In certain embodiments, the invention comprises one or more impactorstages wherein the collection surfaces are on the bottom surface of thestages.

In some embodiments of the invention the orifice containing region andthe particle collecting regions are co-located.

In some embodiments of the invention, the orifice containing regions andthe particle collecting regions are located on different surfaces of theimpactor stages.

In some embodiments of the invention the particle collecting region ison the side wall of the stage while the orifice containing region is onthe bottom surface of the stage.

In some embodiments of the invention the particle collecting region ison the bottom surface of the stage while the orifice containing regionis on the side wall of the stage.

In certain embodiments, the invention comprises a cascade impactordesigned to operate at between about 1 and about 10 liters per minute.

In certain embodiments, the invention comprises a cascade impactordesigned to operate at between about 2 and about 8 liters per minute.

In certain embodiments, the invention comprises a cascade impactordesigned to operate at between about 4 and about 6 liters per minute.

In certain embodiments, the invention comprises impactor stages designedto operate at between about 1 and about 10 liters per minute.

In certain embodiments, the invention comprises impactor stages designedto operate at between about 2 and about 8 liters per minute.

In certain embodiments, the invention comprises impactor stages designedto operate at between about 4 and about 6 liters per minute.

In certain embodiments, the invention comprises a cascade impactor forcollection of particles suspended in air according to their aerodynamicproperties.

In certain embodiments, the invention comprises one or more impactorstages for collection of particles suspended in air according to theiraerodynamic properties.

In certain embodiments, the invention comprises a cascade impactorcapable of collecting and separating aerosol particles havingaerodynamic diameters between about 0.1 and about 15 micrometers.

In certain embodiments, the invention comprises a cascade impactorcapable of collecting and separating aerosol particles havingaerodynamic diameters between about 0.3 and about 12 micrometers.

In certain embodiments, the invention comprises a cascade impactorcapable of collecting and separating aerosol particles havingaerodynamic diameters between about 0.5 and about 8 micrometers.

In certain embodiments, the invention comprises impactor stages capableof collecting and separating aerosol particles having aerodynamicdiameters between about 0.1 and about 15 micrometers.

In certain embodiments, the invention comprises impactor stages capableof collecting and separating aerosol particles having aerodynamicdiameters between about 0.3 and about 12 micrometers.

In certain embodiments, the invention comprises impactor stages capableof collecting and separating aerosol particles having aerodynamicdiameters between about 0.5 and about 8 micrometers.

In certain embodiments, the invention comprises impactor stages capableof collecting liquid aerosols in the bottom regions of stages thatcontain orifices and collection surfaces on the side walls.

In certain embodiments, the invention comprises a method of collectingliquid aerosols in the bottom regions of stages that contain orificesand collection surfaces on the side walls.

To improve the collection efficiency of cascade impactor stages andavoid bouncing of particles after impacting on the collecting surfaces,it is known that a coating material should be applied to the collectionsurfaces. Most methods involve spraying or dipping of collection plates(such as those shown schematically in FIG. 1) with a silicone or othercoating material that will retain the particles on the surface followingimpaction. An apparatus and method described herein allows coating ofthe collection surfaces directly opposing the orifices after theimpactor is assembled and ready for use. The method results in lesscoating material being applied and application only to the areas whereit is needed. Using less coating material reduces the chances that itwill interfere with the analytical methods for the pharmaceutical ortest aerosol.

In certain embodiments, the invention comprises a method of applying acoating material to the collection surface of an impactor stage.

In certain embodiments, the invention comprises a method of applying acoating material simultaneously to the collection surfaces of all stagesof a cascade impactor.

In certain embodiments, the invention comprises a method of applying acoating material to the collection surfaces of one or more impactorstages in the region directly opposing the orifices.

In certain embodiments of the invention, the coating material isselected from the group consisting of adhesives, greases, oils,silicone, Antifoam (Dow Corning, Midland Mich.,), glycerin, andphospholipids.

In certain embodiments, the invention comprises an apparatus forapplying a coating material to the collection surfaces of a cascadeimpactor.

In certain embodiments, the invention comprises an apparatus forapplying a coating material to the collection surfaces of a cascadeimpactor after it is assembled for use.

In certain embodiments of the invention, the coating material isselected from the group consisting of adhesives, greases, oils,silicone, Antifoam (Dow Corning, Midland Mich.), glycerin, andphospholipids.

In certain embodiments of the invention, the coating material is asilicone liquid.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 is a cross-sectional schematic view of a typical cascade impactorused for pharmaceutical aerosol sampling.

FIG. 2 is a cross-sectional view of an exemplary stage of one embodimentof the invention wherein the orifices are in the side wall of theimpactor stage.

FIG. 3 is a cross-sectional view of an exemplary stage of one embodimentof the invention wherein the orifices are in the bottom of thecollection stage.

FIG. 4 shows cross-sectional views of a final filter stage for holding afilter within the impactor. FIG. 4 is a longitudinal view of the stagewith one impactor stage mounted therein. FIG. 4A is a transverse viewthrough section A on FIG. 4.

FIG. 5 is a cross-sectional view of a stage for connecting an externalfinal filter.

FIG. 6 is a cross-sectional view of an embodiment of the inventionwherein the orifices are on the side walls of the collection stages.

FIG. 7 is a cross-sectional view of an embodiment showing two assembledstages wherein the orifices are in the bottoms of the collection stages.

FIG. 8 is a cross-sectional view of an exemplary stage of one embodimentof the invention wherein the orifices are in the side wall of thecollection stage with labels for dimensions referred to in some of theexamples.

FIG. 9 is a schematic diagram of an apparatus for applying coatingmaterials to the collection surfaces of an assembled cascade impactor.

FIG. 10 is a graph of the particle size generated with time derived fromthe equations of Mugele (Mugele, R. A and HD Evans. Droplet SizeDistribution in Sprays, Indust. and Engineering Chem. 43(6):1317-1324,1951).

FIG. 11 is a cross-sectional view of another embodiment of the inventionwherein the orifices are on the side walls of the collection stages.

FIG. 12 is a graph of the size distributions for an aerosol sampled byboth an Andersen cascade impactor and the embodiment described inExample 1.

FIG. 13 is a graph comparing the size distribution of an aerosolmeasured by the embodiments described Example 1 and in Example 5.

FIG. 14 is a graph comparing the size distribution of a liquid aerosolsampled by the embodiment described in Example 5 and a Delrin Andersenimpactor.

FIG. 15 is a graph of the size distribution of a coating aerosolproduced according to Example 10.

FIG. 16 is a graph comparing the size distributions of an aerosolproduced and collected according to Example 11.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides embodiments for a novel cascade impactor.The stages of the impactor serve both as orifice plates and collectionsurfaces, thus minimizing the analytical requirements whilesimultaneously accounting for interstage particle losses. The orificesmay be placed in the bottom surface of the collection stages, on theside walls of the collection stages, or a combination of both, dependingupon the desired sampling flow rate. However, as discussed below, otherconfigurations are also contemplated.

As used herein, the terms “comprising”, “including”, “such as”, and “forexample” are used in their open, non-limiting sense.

As used herein, the term “about” is used synonymously with“approximately.” As such, values ranging between ±20% of the statedvalue may be considered equivalent for pressures and flow rates and ±30%for particle sizes.

As used herein, the term “aerosol” is defined as a suspension of solidparticles or liquid droplets in air. Such a suspension is not requiredto be stable for any specific length of time, as it is recognized in theart that inhalation drug delivery devices (e.g., nebulizers, pressurizedmetered dose inhalers, dry powder inhalers, and the like) are capable ofproducing and emitting an extremely wide range of particle and dropletsizes.

As used herein, the terms atomizer and nebulizer are usedinterchangeably.

As used herein, the term “D₅₀” is defined as the median diameter. On animpactor stage 50% of the particles collected will be larger than theD₅₀ and 50% will be smaller. This is also referred to as the cutoffdiameter for the stage.

As used herein, the terms “cutpoint”, “cut size”, and “cutoff diameter”refer to the median collection diameter for a given stage in theimpactor.

As used herein, the term “Cunningham slip correction” refers to thecorrection to the particle diameter when it is close to the mean freepath of the gas molecules. For particles greater than 1 micrometer, thecorrection is small, but becomes more significant below that size.

Calculation of the orifice diameters and corresponding flow rates toachieve desired cutoff diameters for the stages in an impactor may beaccomplished using equations known in the art and presented by Marpleand Willeke (Marple V A, Willeke K. Inertial impactors: theory, design,and use. In: Fine Particles, Aerosol Generation, Measurement, Sampling,and Analysis. Liu BYH ed. Academic Press, NY, 1975 pp 412-446) which ishereby incorporated by reference. Essentially, the cutoff diameter of50% efficiency may be calculated from

${Stk}_{50} = \frac{4\rho_{p}{QCD}_{50}^{2}}{9\pi\; n\;\mu\; W^{3}}$

where ρ_(p) is the particle density (assumed to be 1 for measuringaerodynamic diameters), Q is the flow rate through the stage in cm³/sec,C is the Cunningham slip correction, n is the number of orifices in thestage, μ is the viscosity of the sampled air (e.g., 1.81×10⁻⁴ poise atnormal temperature and pressure), W is the diameter, in cm, of a singleorifice in the stage, and Stk₅₀ is the Stokes number at 50% collectionefficiency.

This equation may be rearranged and solved for the product of the cutoffdiameter times the square root of the Cunningham slip correction asfollows:

${\sqrt{C}D_{50}} = {\sqrt{\frac{9\pi\;\mu\; W^{3}}{4Q}}*\sqrt{{Stk}_{50}}}$

For round jets operating at Reynolds numbers greater than 100, √{squareroot over (Stk₅₀)} is approximately 0.47.

Turning now to the figures, FIG. 1 is a cross-sectional schematic viewof a typical cascade impactor used for pharmaceutical aerosol sampling(Andersen Cascade Impactor, available from various manufacturers, e.g.Westech Instruments, Marietta, Ga.; Copley Scientific, Nottingham, UK;Thermo Fisher Scientific, Waltham, Mass.). Each stage has multipleorifices, ranging from 96 to 400 in number. The collection surfaces areseparate metal plates that are separately inserted on supportingstandoffs machined into each stage. O-rings seal each stage when thedevice is assembled and springs are used to compress the stages togetherto prevent air from leaking in between the stages during sampling.

FIG. 2 depicts an exemplary impactor stage 20 of one embodiment of theinvention. One or more holes 21 are drilled or molded within the sidewall of the stage. These one or more holes comprise the orifices throughwhich the particle-laden aerosol passes before being collected on adownstream collection surface. When more than one orifice is used, theorifices may be positioned equidistant around the circumference of thestage. The inner surface 24 of the stage comprises the collectionsurface for the preceding stage in an assembled cascade impactor. Thecollection surface for the stage shown in the figure is located on thenext stage in the cascade. An O-ring 23 is positioned in a groove 25 toensure a slidable air-tight seal of the stage with the next concentricstage in the cascade.

The stage can be machined from any metal material including stainlesssteel, aluminum, or brass. Alternatively, a variety of plastic materialsmay be used, including acetal resins (e.g., DELRIN, E. I. du Pont deNemours and Company, Wilmington, Del.), or other solid polymericmaterials (e.g., NYLON, TEFLON, E. I. du Pont de Nemours and Company,Wilmington, Del.).

In some embodiments, a combination of plastic and metal materials may beused.

Also shown in FIG. 2 are three design dimensions; the orifice diameterW, the spacing S between the orifice exit and the downstream collectionsurface, and the thickness T of the orifice. The diameter of the holesor orifices is referred to as W in the design equations presented above.

In some embodiments of the invention, the distance from the exit of theone or more orifices to the collection surface on the next stage (S)divided by the diameter of the orifice (W), S/W, is less than or equalto about 5.

In some embodiments, the ratio of the distances S/W is less than orequal to about 2.

In some embodiments, the ratio of the distances S/W is less than orequal to about 1.

In some embodiments, the ratio of the distances S/W is less than orequal to about 0.5.

In some embodiments the ratio of the distances S/W is greater than 1.

In still other embodiments, the ratio of the distances S/W is equal to1.

In some embodiments, ratio of the distances S/W is between 0.5 and 5.

In some embodiments, the ratio of the distances S/W is equal to about0.5, about 1, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5,about 4.0, about 4.5, or about 5.0.

In some embodiments, the ratio of the thickness of the orifice to thediameter of the orifice (T/W) is equal to about 1.

In other embodiments T/W is greater than 1.

FIG. 3 depicts an exemplary impactor stage 30 of one embodiment of theinvention. One or more holes 31 are drilled or molded on the bottomsurface of the stage. These holes comprise the one or more orificesthrough which the particle-laden aerosol passes before being collectedon a downstream collection surface. The diameter of the holes isreferred to as W in the design equations presented above. The innersurface 35 of the stage comprises the collection surface for thepreceding stage. A raised portion 34 is machined or molded around theinside edge of the base of the stage to establish the desired distance(S) from the exit of the orifices on the preceding stage to thecollection surface 35 on the illustrated stage. An O-ring 33 ispositioned in a groove 36 to ensure a slidable air-tight seal of thestage with the next concentric stage in the cascade. Also shown in thisfigure are optional indentations 32 which are useful for assembly anddisassembly of the impactor. Similar indentations may be incorporated,as needed on other embodiments and stages as presented and describedherein.

In some embodiments of the invention, the distance from the exit of theone or more orifices to the collection surface on the next stage (S)divided by the diameter of the orifice (W), S/W, is less than or equalto about 5.

In some embodiments, the ratio of the distances S/W is less than orequal to about 2.

In some embodiments, the ratio of the distances S/W is less than orequal to about 1.

In some embodiments, the ratio of the distances S/W is less than orequal to about 0.5.

In some embodiments the ratio of the distances S/W is greater than 1.

In still other embodiments, the ratio of the distances S/W is equal to1.

In some embodiments, ratio of the distances S/W is between 0.5 and 5.

In some embodiments, the ratio of the distances S/W is equal to about0.5, about 1, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5,about 4.0, about 4.5, or about 5.0.

In some embodiments, the ratio of the thickness of the orifice to thediameter of the orifice (T/W) is equal to about 1.

In other embodiments T/W is greater than 1.

The stage can be machined from any metal material including stainlesssteel, aluminum, or brass. Further, a variety of plastic materials maybe used, including acetal resins (e.g., DELRIN, E. I. du Pont de Nemoursand Company, Wilmington, Del.), or other solid polymeric materials(e.g., NYLON, TEFLON, E. I. du Pont de Nemours and Company, Wilmington,Del.).

In certain embodiments of the invention, a combination of metal andplastic materials may be used.

FIG. 4 depicts a final filter stage 40 in which a filter 44 is mountedand retained by a pressure from the nested stage 41 above and or anO-ring 42. The filter is further supported by a mesh or screen 43. Avacuum source is connected with an optionally threaded fitting at 45.Also shown in FIG. 4 is the collection surface 48 for the aerosolimpacted by the orifices in nested stage 41. FIG. 4A shows a transversesection through FIG. 4 at A. Protruding portions 46 of the precedingstage may be used to apply pressure to keep the O-ring 42 and filter 44in place. Openings 47 allow air to flow from the preceding stage to thecollection filter.

The stages can be machined from any metal material including stainlesssteel, aluminum, or brass. Further, a variety of plastic materials maybe used, including acetal resins (e.g., DELRIN, E. I. du Pont de Nemoursand Company, Wilmington, Del.), or other solid polymeric materials(e.g., NYLON, TEFLON, E. I. du Pont de Nemours and Company, Wilmington,Del.). In some embodiments, a combination of metal and plastic materialsmay be used.

FIG. 5 depicts a final stage 500 that allows connection of a cascadeimpactor as described herein to an external filter holder. An optionalthreaded connection 503 is located in the bottom, or in the side wall,where a vacuum source may be attached. One or more protrusions 501support the preceding stage and ensure an airflow path to the collectionfilter.

The stage can be machined from any metal material including stainlesssteel, aluminum, or brass. Further, a variety of plastic materials maybe used, including acetal resins (e.g., DELRIN, E. I. du Pont de Nemoursand Company, Wilmington, Del.), or other solid polymeric materials(e.g., NYLON, TEFLON, E. I. du Pont de Nemours and Company, Wilmington,Del.). In some embodiments, a combination of metal and plastic may beused.

FIG. 6 depicts a cross-sectional diagram of one embodiment of a fullyassembled cascade impactor comprising 4 impaction stages and an externalfinal filter stage. As shown, each stage is made to slidably seal withthe next stage in the cascade by means of O-rings 103, 203, 303, and 403situated in grooves machined or molded into the sides of the stages.After assembly, alternating stages may be rotated to establish an angleof between approximately 30 degrees to approximately 90 degrees, toassure that the orifices are not coplanar. In usage, an inhaler or otherrespiratory drug delivery device, for example, is connected to the inlet601. Particle-laden air is pulled through the assembly by an externalvacuum source connected at 503. As particle-laden air passes through thesuccessive stages, 100, 200, 300, and 400, it carries the particlesthrough each stage's orifices 101, 201, 301, and 401. Particles areimpacted on their respective collection surfaces 102, 202, 302, and 402downstream from the orifices as previously described according to theirinertial properties. In this way, the aerosol particles are separated byaerodynamic diameter.

The stages can be machined from any metal material including stainlesssteel, aluminum, or brass. Further, a variety of plastic materials maybe used, including acetal resins (e.g., DELRIN, E. I. du Pont de Nemoursand Company, Wilmington, Del.), or other solid polymeric materials(e.g., NYLON, TEFLON, E. I. du Pont de Nemours and Company, Wilmington,Del.). In some embodiments, a combination of metal and plastic may beused.

Following collection of the sample, the impactor is disassembled and theamount of drug, or other characteristic of the particles, on eachcollection surface is assayed by an appropriate analytical method. Theresulting particle size distribution or other descriptive parameters maybe calculated from the analytical results.

If the impactor is used for environmental sampling, the inlet wouldremain open to the environment during sample collection and the stageswould be assayed for the chemical or particle of interest.

The airflow rate through the assembled, operating cascade impactors iscontrolled externally with valves and or flow meters as is known in theart, and is determined from calculations of the stage parameters and theequations presented herein.

In some embodiments, the invention comprises cascade impactor comprisinga series of one or more concentrically-arranged collection stages and aterminating filter or filter adapting stage, each collection stagecomprising an elongated structure with a cylindrical shape, saidelongated structure having a top end and a bottom end, the walls of saidelongated structure having an inner surface and an outer surface andfurther characterized by a single inner diameter, a first outerdiameter, and a second outer diameter, the top end being open and thebottom end being closed with a flat surface said elongated structurefurther comprising a region wherein the second outer diameter is lessthan the first outer diameter to form a orifice-containing region, thewall of said elongated structure further comprising at least one orificepositioned in said orifice-containing region and perpendicular to saidwall and through which aerosol-containing air flows, the first outerdiameter of said elongated structure being sized to fit within andslidably seal within the inner diameter of the next stage in the series.

In certain embodiments, the particles entrained in the sampled air arecollected on the inner surface of the wall of the next stage in theseries.

In some embodiments, orifices are placed equidistant around thecircumference of the stage in the orifice-containing region.

In certain embodiments, the filter stage is further sized to receive theouter diameter of the last collection stage in said series.

In still other embodiments, the filter stage is connected externallyfrom the series of stages.

In certain embodiments, the impactor is designed to operate at a flowrate between about 1 and about 15 lpm.

In certain embodiments, the impactor is designed to operate at a flowrate between about 1 and about 10 lpm.

In other embodiments, the impactor is designed to operate at a flow ratebetween about 2 and about 8 lpm.

In other embodiments, the impactor is designed to operate at a flow ratebetween about 4 and about 6 lpm.

In other embodiments, the impactor is designed to separate particleswith sizes between about 0.1 and about 15 micrometers aerodynamicdiameter.

In other embodiments, the impactor is designed to separate particleswith sizes between about 0.3 and about 12 micrometers aerodynamicdiameter.

In other embodiments, the impactor is designed to separate particleswith sizes between about 0.5 and about 8 micrometers aerodynamicdiameter.

In some embodiments of the invention, the distance from the exit of theone or more orifices to the collection surface on the next stage (S)divided by the diameter of the orifice (W), S/W, is less than or equalto about 5.

In some embodiments, the ratio of the distances S/W is less than orequal to about 2.

In some embodiments, the ratio of the distances S/W is less than orequal to about 1.

In some embodiments, the ratio of the distances S/W is less than orequal to about 0.5.

In some embodiments the ratio of the distances S/W is greater than 1.

In still other embodiments, the ratio of the distances S/W is equal to1.

In some embodiments, ratio of the distances S/W is between 0.5 and 5.

In some embodiments, the ratio of the distances S/W is equal to about0.5, about 1, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5,about 4.0, about 4.5, or about 5.0.

In some embodiments, the ratio of the thickness of the orifice to thediameter of the orifice (T/W) is equal to about 1.

In other embodiments T/W is greater than 1.

FIG. 7 shows two nested impactor stages wherein the orifices andcollection surfaces are on the bottoms of the stages. Aerosol enteringthe first stage passes through that stage's orifice 71 and some of theparticles impact on the collection surface 72. The remainingnon-impacted aerosol continues through the orifices 75 in the next stageand onto a collection surface or filter as may be configured using thedesigns presented herein. O-rings 73 and 74 serve to slidably seal thestages and prevent leakage of air during sampling. A raised portion 76and 77 is machined or molded into each stage to establish the desiredspacing between the exit of the orifices and the collection surface.

Additional stages may be designed and constructed to assemble a cascadeimpactor covering a wide range of cut-points according to the disclosurepresented herein.

In some embodiments, the invention comprises a cascade impactorcomprising a series of one or more concentrically-arranged collectionstages and a terminating filter stage, each collection stage comprisingan elongated structure with a cylindrical shape, said elongatedstructure having an open top end and a bottom end containing at leastone orifice through which aerosol-containing air flows, the walls ofsaid elongated structure having an inner surface and an outer surfaceand further characterized by a raised portion inside said bottom end,said raised portion sized to establish an orifice-to-collection surfacedistance, the outer diameter of said elongated structure being sized tofit within and slidably seal within the inner diameter of the next stagein the series.

In certain embodiments, the particles entrained in the sampled air arecollected on the inner surface of the bottom end of the next stage inthe series.

In some embodiments, filter stage is further sized to receive the outerdiameter of the last collection stage in the series.

In some embodiments, the filter stage is connected externally from theseries of stages.

In certain embodiments, the impactor is designed to operate at a flowrate between about 1 and about 15 lpm.

In certain embodiments, the impactor is designed to operate at a flowrate between about 1 and about 10 lpm.

In still other embodiments, the impactor is designed to operate at aflow rate between about 2 and about 8 lpm.

In still other embodiments, the impactor is designed to operate at aflow rate between about 4 and about 6 lpm.

In certain embodiments, the impactor is designed to separate particleswith sizes between about 0.1 and about 15 micrometers aerodynamicdiameter.

In still other embodiments, the impactor is designed to separateparticles with sizes between about 0.3 and about 12 micrometersaerodynamic diameter.

In still other embodiments, the impactor is designed to separateparticles with sizes between about 0.5 and about 8 micrometersaerodynamic diameter.

In some embodiments of the invention, the distance from the exit of theone or more orifices to the collection surface on the next stage (S)divided by the diameter of the orifice (W), S/W, is less than or equalto about 5.

In some embodiments, the ratio of the distances S/W is less than orequal to about 2.

In some embodiments, the ratio of the distances S/W is less than orequal to about 1.

In some embodiments, the ratio of the distances S/W is less than orequal to about 0.5.

In some embodiments the ratio of the distances S/W is greater than 1.

In still other embodiments, the ratio of the distances S/W is equal to1.

In some embodiments, ratio of the distances S/W is between 0.5 and 5.

In some embodiments, the ratio of the distances S/W is equal to about0.5, about 1, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5,about 4.0, about 4.5, or about 5.0.

In some embodiments, the ratio of the thickness of the orifice to thediameter of the orifice (T/W) is equal to about 1.

In other embodiments T/W is greater than 1.

FIG. 8 is a cross-sectional view of an exemplary stage of an embodimentof the invention wherein the orifices are in the side wall of thecollection stage. Shown in the figure are labels for dimensions referredto in some examples presented below.

In some embodiments of the invention, the distance from the exit of theone or more orifices to the collection surface on the next stage (S)divided by the diameter of the orifice (W), S/W, is less than or equalto about 5.

In some embodiments, the ratio of the distances S/W is less than orequal to about 2.

In some embodiments, the ratio of the distances S/W is less than orequal to about 1.

In some embodiments, the ratio of the distances S/W is less than orequal to about 0.5.

In some embodiments the ratio of the distances S/W is greater than 1.

In still other embodiments, the ratio of the distances S/W is equal to1.

In some embodiments, ratio of the distances S/W is between 0.5 and 5.

In some embodiments, the ratio of the distances S/W is equal to about0.5, about 1, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5,about 4.0, about 4.5, or about 5.0.

In some embodiments, the ratio of the thickness of the orifice to thediameter of the orifice (T/W) is equal to about 1.

In other embodiments T/W is greater than 1.

In another aspect of the invention, a novel apparatus and method hasbeen developed to apply a suitable coating to the collection surfaces ofthe stages of the impactor embodiments described herein, or to thecollection surfaces of other impactors as are known in the art, in theregion directly opposing the orifices of the stages. The coating isdeposited exactly where the aerosol to be analyzed will be impacted anddeposited. The method and apparatus provide for limiting application ofextraneous coating to any other part of the impactor or collectionsubstrates. The method and apparatus serve to form an aerosol of thecoating material. Subsequent sampling of the coating aerosol through thecascade impactor under normal operating conditions ensures an ample anduniform coating.

It has been discovered that a very wide aerosol size distribution ofcoating-material droplets is required so that each impactor stage isuniformly coated. Such an aerosol can be generated by severalatomization techniques, including rotary (e.g., spinning disc),hydraulic (e.g., liquid spray under pressure), pneumatic (e.g., twinfluid atomization), electrohydrodynamic, vibrating orifice, vibratingmesh, or other atomization techniques as are known in the art. Anaerosol may also be produced by dissolution or suspension of the coatingmaterial in a suitable propellant (e.g., chlorofluorocarbon, hydrogenchlorofluorocarbon, hydrocarbon, nitrogen, carbon dioxide, etc.) andgenerating a spray from the resulting propellant pressure.

In some embodiments, the invention comprises a method of simultaneouslycoating the collection surfaces of an assembled cascade impactorcomprising creating an aerosol comprising droplets of a liquid coatingmaterial, drawing said aerosol into the impactor with a vacuum source,and depositing said droplets of said coating material on the collectionsurfaces of the impactor stages.

Production of a broad size distribution often requires variation of someproperty that affects atomized droplet size

In some embodiments of the invention, the method of coating the stagesof the impactor comprises continually varying the viscosity of thecoating material during the generation of the coating material aerosol.

In some embodiments of the invention, the method of coating the stagesof the impactor comprises continually varying the density of the coatingmaterial during the generation of the coating material aerosol.

In still other embodiments of the invention, the method of coating thestages of the impactor comprises varying the input energy to the coatingaerosol generator during the generation of the coating material.

The input energy to the coating aerosol generator may be varied in anumber of ways depending upon the generator employed (e.g., rotationalspeed for a rotary atomizer, frequency of vibration for a vibratingorifice or vibrating mesh atomizer, temperature of the propellant for apropellant based atomizer, or pressure for a hydraulic or pneumaticatomizer).

In some embodiments of the invention the method of coating the impactorcollection surfaces comprises varying the air pressure to a pneumaticnebulizer.

In some embodiments of the invention the method of coating the impactorcollection surfaces comprises varying the air pressure to a disposablemedical nebulizer.

In certain embodiments of the invention, the compressed air supply forthe pneumatic nebulizer is stored in a rechargeable pressure container.

FIG. 9 is a schematic diagram of an apparatus for applying coatingmaterials to the collection surfaces of an assembled cascade impactor. Arechargeable, pressurized air container 901 with a valve 902 isconnected via a coupling 903 to a compressed air nebulizer 905. Thenebulizer is loaded with a quantity of liquid coating material 904. Uponopening the valve 902, the air pressure within the container is releasedthrough the nebulizer and an aerosol is produced at the outlet 906.Initially the aerosol is comprised of small droplets, but the sizesbecome larger as the pressure decreases with continual release of theair from the container.

FIG. 10 shows a correlation of the particle size produced from theapparatus of FIG. 9 with time as the air pressure within the containeris dissipated from about 145 psig to about 15 psig. This relationshipwas derived from the method of Mugele (Mugele, R. A and H D Evans.Droplet Size Distribution in Sprays, Indust. and Engineering Chem.43(6):1317-1324, 1951; hereby incorporated by reference) using thecharacteristics of the nebulizer (jet-orifice diameter); the coatingliquid viscosity, density, and surface tension; the gas viscosity; andthe air pressure in the container. The relationship in FIG. 10 showsthat the mean droplet diameter varies from about 2.5 to 18 micrometerswhen the coating apparatus of FIG. 9 is operated for about 15 seconds.

Air pressure is varied by charging a pressure container with compressedair, then exhausting the air supply from the pressurized containerthrough the nebulizer. The volume of the container is selected toprovide a sufficiently long operating time to aerosolize a given volumeof coating material. Multiple actuations of the apparatus may used toaerosolize additional coating material. A broad size distribution ofaerosol is produced as the pressure changes from high to low.

In some embodiments of the invention, the container of the apparatus ispressurized to a pressure up to approximately 10 times the recommendedoperating pressure of the nebulizer.

In other embodiments of the invention, the container of the apparatus ispressurized to a pressure up to approximately 5 times the recommendedoperating pressure of the nebulizer.

In still other embodiments of the invention, the container ispressurized to a pressure up to 2 times the recommended operatingpressure of the nebulizer.

Most commercial cascade impactors are not well suited for the collectionof liquid droplet aerosols. This is because the collection surfaces areoften horizontal plates and excess liquid remaining in regions of highvelocity airflow can be re-entrained if excessive amounts are deposited.FIG. 11 shows an assembled embodiment of the invention utilizing thestage configuration of FIG. 8. This example embodiment has an inletstage 1101, 3 collection stages 1102, 1103, and 1104 and an adapter 1105for a final filter (not shown). O-rings 1106, 1107, and 1108 createslidable seals for assembling and disassembling the impactor. Afterassembly, the stages are rotated from an angle between approximately 30degrees and approximately 90 degrees so that the orifices are offsetfrom a common vertical plane. In operation with a liquid dropletaerosol, excess liquid may drip down the sides of the collectionsurfaces 1109, 1110, and 1111 to accumulate at the bottoms of thecollection stages. In order to properly account for this collectedmaterial, this embodiment of the invention creates spaces 1112, 1113 and1114 to accumulate the liquid at each stage without it beingre-entrained by the high velocity airflow near the orifices. As shown inthe figure, these spaces are created by resting the edge of one stage onthe step-like portion of the next succeeding stage in the series.Further, the final stage contains an annular groove 1115 to prevent anyaccumulated liquid from passing onto the filter stage. This exampleembodiment allows for collection of significantly more liquid materialthan would be collectable on a horizontal flat surface, which in turncan help overcome low analytical detection limits. This embodiment isalso well suited for use with dried aerosol particles.

The stages can be machined from any metal material including stainlesssteel, aluminum, or brass. Further, a variety of plastic materials maybe used, including acetal resins (e.g., DELRIN, E. I. du Pont de Nemoursand Company, Wilmington, Del.), or other solid polymeric materials(e.g., NYLON, TEFLON, E. I. du Pont de Nemours and Company, Wilmington,Del.). In some embodiments, a combination of metal and plastic may beused.

Additional stages may be designed and constructed to assemble a cascadeimpactor covering a wider range of cut-points according to thedisclosure presented herein.

In some embodiments, the invention comprises a cascade impactorcomprising a series of one or more concentrically-arranged collectionstages and a terminating filter or filter adapter stage, each collectionstage comprising an elongated structure with a cylindrical shape, saidelongated structure having a top end and a bottom end, the walls of saidelongated structure having an inner surface and an outer surface andfurther characterized by a first inner diameter, a second innerdiameter, a first outer diameter and a second outer diameter, the topend of each stage being open and the bottom end being closed with a flatsurface, said elongated structure further comprising a region whereinthe second outer diameter is less than the first outer diameter to forma orifice-containing region, and a region wherein the first innerdiameter is greater than the second inner diameter forming a stepfeature, the wall of said elongated structure further comprising one ormore orifices positioned in said orifice-containing region andperpendicular to said wall and through which aerosol-containing airflows, the first outer diameter of said elongated structure being sizedto fit within and slidably seal within the first inner diameter of thenext stage and rest upon the step feature of said next stage in theseries.

In certain embodiments with more than one orifice present, the orificesare spaced equidistant around the circumference of the stage wall.

In some embodiments, the first and second inner diameters are the samefor the first stage.

In certain embodiments, the particles entrained in the sampled air arecollected on the inner surface of the wall of the next stage in theseries.

In some embodiments, the particles entrained in the sampled air arerecovered from the bottom of the next stage in the series.

In certain embodiments, a filter stage is further sized to receive thefirst outer diameter of the last collection stage in said series.

In still other embodiments, a filter stage is connected externally fromthe series of stages.

In certain embodiments, the impactor is designed to operate at a flowrate between about 1 and about 15 lpm.

In certain embodiments, the impactor is designed to operate at a flowrate between about 1 and about 10 lpm.

In other embodiments, the impactor is designed to operate at a flow ratebetween about 2 and about 8 lpm.

In other embodiments, the impactor is designed to operate at a flow ratebetween about 4 and about 6 lpm.

In other embodiments, the impactor is designed to separate particleswith sizes between about 0.1 and about 15 micrometers aerodynamicdiameter.

In other embodiments, the impactor is designed to separate particleswith sizes between about 0.3 and about 12 micrometers aerodynamicdiameter.

In other embodiments, the impactor is designed to separate particleswith sizes between about 0.5 and about 8 micrometers aerodynamicdiameter.

EXAMPLES

The following examples are intended to be illustrative of variousembodiments of the invention and are not intended to be limiting innature.

Example 1

A cascade impactor with 4 collection stages and a filter stage wasconstructed according to the embodiment depicted in FIG. 3 and FIG. 7and described in Table 1. This particular embodiment was designed tooperate at 4 liters per minute total air flow. For the example describedherein, clear plastic disks, 3.5 mil thick, were placed on each stage atthe points of particle impaction in the cascade impactor to serve asparticle collection substrates and allow for subsequent microscopicevaluation of the collected particles.

TABLE 1 Dimensions of one embodiment of a cascade impactor as describedherein whereby one or more orifices are on the bottom surfaces of theimpactor stages. The dimensions are referenced to FIG. 3. Cutoff SizeDimensions [inches] No. D₅₀(C)^(1/2) Stage A B L W T S Orifices[micrometers] 1 0.50 0.339 1.25 0.1850 0.1850 — 1 6.95 2 0.75 0.50 1.1250.1130 0.1130 0.370 2 4.71 3 1.00 0.75 1.00 0.1130 0.1130 0.226 1 3.36 41.25 1.00 1.00 0.0390 0.0390 0.226 1 1.02 Filter 1.50 1.25 1.50 — —0.078 — <1.02 A = Nominal Outer Diameter [inches] B = Nominal InnerDiameter [inches] L = Length [inches] W = Orifice Diameter [inches] T =Orifice Length [inches] S = Orifice to Collection Surface Spacing[inches]

Example 2

The apparatus of FIG. 9 was assembled. The container had a volume ofabout 475 ml and was pressurized to about 145 psig. A 1:100 dilution ofsilicone Antifoam (Dow Corning 1520) in water was added to a VixOnenebulizer (Westmed, Greenwood Village, Colo.). The valve was opened andan aerosol of the diluted silicone coating material was generated andsampled into the cascade impactor of Example 1 at a flow rate of 4 lpm.This method was repeated one more time, resulting in a total of 0.8 mgto 1.0 mg of coating material being deposited on the plastic diskcollection surfaces of the impactor. The plastic disks described inExample 1 were removed and evaluated. The silicone was uniformlydistributed (about 0.1 to 0.2 mg) on each collection substrate.Microscopic examination of the substrates indicated a much more uniformcoating than when compared to conventional application by an eyedropper.The coating thickness was uniform and adequate for trapping particles,and the coated area opposing the orifices was about 1.5 to 2 times thediameter of the respective orifices for the stage.

Example 3

The impactor of Example 1 was once again reassembled, with clean clearplastic disks as described in Example 1. To coat the collectionsubstrate surfaces, an aerosol of silicone Antifoam diluted 1:100 inwater was produced by the apparatus depicted in FIG. 9 and the methoddescribed in Example 2. The Antifoam coating aerosol was sampled by thecascade impactor for 15 seconds with a flow rate of 4 l/min. Immediatelyfollowing this, 5.1 mg of a test aerosol comprising a dry powderformulation of placebo measles vaccine was aerosolized into a spacer(Aerochamber Max, Trudell Medical, London, Ontario, Canada) and sampledinto the impactor with a flow rate of 4 lpm for 30 seconds.

Example 4

After sampling the aerosol as described in Example 3, the plastic diskswere removed and examined under the microscope to evaluate the size ofparticles collected on each stage. The results are shown in Table 2. Thecut size for each stage was determined by measuring the diameters of theobserved placebo vaccine aerosol particles collected on each individualsubstrate and estimating the median and range of the diameters. The datain Table 2 indicate that the cascade impactor separated the aerosolparticles into size fractions as designed according to embodiments ofthe invention, with the cutoff diameter in the middle of the size rangeof particles collected.

TABLE 2 Microscopic Classification of the Particles Collected on theStages and Determination of the Cut Sizes of the Stages of the ImpactorEmbodiment Described in Example 1. Estimated Geometric Cut Point StageSmallest Largest Mean [micrometers] 1 1.5 14.4 7 6.95 2 1 6.4 5 4.71 31.3 4.5 3.5 3.36 4 0.7 2.8 1 1.02 Filter <1 <1 — —

Example 5

A cascade impactor with orifices and collection surfaces located on theside walls of the stages was constructed according to the parameters inTable 3 and single-stage embodiments shown in FIG. 2 and FIG. 8. Clearplastic disks were placed at the points of particle impaction to serveas particle collection surfaces. To coat the collection surfaces, anaerosol of Dow Antifoam diluted 1:100 in water was produced by theapparatus depicted in FIG. 9. The Antifoam coating aerosol was sampledby the cascade impactor for 15 seconds with a flow rate of 4 l/min. 5.1mg of a placebo dry powder formulation of measles vaccine wasaerosolized into a spacer (Aerochamber Max, Trudell Medical, London,Ontario, Canada) and sampled into the impactor with a flow rate of 4l/min for 30 seconds.

TABLE 3 Dimensions of one embodiment of a cascade impactor as describedherein whereby one or more orifices are on the side walls of theimpactor stages. The dimensions are referenced to FIG. 8. Dimensions[inches] Cutoff Size Orifice No. D₅₀(C)^(1/2) Stage A B C W E F DiameterOrifices [micrometers] 1 1.25 — 0.3390 0.1285 0.5960 1.1100 0.1285 36.96 2 1.75 1.25 1.1100 0.1015 1.3130 1.7190 0.1015 2 4.03 3 2.25 1.751.7190 0.0625 1.8440 2.0940 0.0625 2 1.99 4 2.50 2.25 2.0940 0.03902.1720 2.3280 0.0390 2 1.02 5 2.75 2.50 2.3280 0.0225 2.3730 2.46300.0210 4 0.66 Filter 3.00 2.75 2.4630 — 3 3 — — <0.66 A = Nominal outerdiameter [inches] B = Nominal inner diameter [inches] C = Inner diameter[inches] W = Orifice diameter [inches] E = Outer diameter [inches] F =Second Inner Diameter of the Next Stage [inches] The overall height ofeach stage in this example is approximately 1.50 inches.

Example 6

After collection, the clear disks were examined under a microscope. Theresulting sizes of particles collected on each stage confirmed thecalculated cutoff diameters for the stages and showed that theembodiment containing orifices in the side walls of the stages performscomparably to the embodiment in which the orifices are in the bottoms ofthe stages.

Example 7

An aerosol of ammonium fluorescein was produced in a wind tunnel bynebulizing a 5% ammonium fluorescein solution with an Aeroneb nebulizer(Nectar, San Carlos, Calif.) and allowed to dry to solid particles inthe wind tunnel.

Ammonium fluorescein was chosen because of its widespread and long-knownuse in the art as a sensitive tracer material. It is very soluble inwater, forms non-hygroscopic particles, and is easily analyzed with aspectrometer or a fluorometer down to a concentration of 1 nanogram permilliliter.

The dried aerosol was sampled from the wind tunnel with the impactor ofExample 1 and the mass of aerosol deposited on each stage was analyzedwith a Turner Biosystems Picofluor fluorometer (Sunnyvale, Calif.).Clear plastic disks described in Example 1 were not used or needed forthe collection of the fluorescein aerosol. An Andersen cascade impactor(Westech Instruments, Atlanta, Ga.) was also used to sample the aerosolfrom the wind tunnel and the mass collected on each stage was similarlyanalyzed. The size distributions as measured by both impactors wereplotted and compared (FIG. 12), and indicated very good agreementbetween the two impactors.

Example 8

A cascade impactor was constructed according to Example 5 and Table 3.An aerosol of ammonium fluorescein produced as described in Example 7was sampled with the impactors of Examples 1 and 5. The resulting sizedistribution plot (FIG. 13) indicates good agreement between the twoimpactors.

Example 9

A liquid aerosol of water and ammonium fluorescein is nebulized with aBird Micronebulizer (Hudson RCI, Temecula Calif.). The impactor ofExample 5 and a Delrin Andersen impactor (Westech Instruments, Atlanta,Ga.) specially designed for liquid aerosols are used to sample aerosolfrom the micronebulizer. The results are analyzed fluorometrically as inExample 7. A plot (FIG. 14) of the size distributions as measured byeach of the impactors shows that the impactors are similar in themeasured size distribution.

Example 10

The apparatus of Example 2 was assembled. A 1:10 dilution of siliconantifoam in water with 0.01% ammonium fluorescein added as a tracer wasadded to a VixOne nebulizer. The apparatus was pressurized to about 145psi. The valve was opened and the aerosol produced was sampled into theimpactor of Example 4 at 4 l/min. This method was repeated five moretimes, and then each of the impactor stages was analyzedfluorometrically. The size distribution is shown in FIG. 15. The massmedian diameter of the grease aerosol was 3.92 micrometers, and thestandard geometric deviation was 2.09. The amount of silicone greasedeposited on each stage was calculated from analysis of the ammoniumfluorescein tracer. Table 4 gives the approximate coverage under eachimpactor orifice. This aerosol was suitable for depositing a functionalcoating on each of the stages.

TABLE 4 Coverage of impactor stages with silicone grease Stage WeightGrease (mg/sq. in.) 1 20 2 98 3 260 4 250 5 69

Example 11

The apparatus of Example 2 was assembled. A 1:10 dilution of siliconantifoam in water was added to a VixOne nebulizer. The device waspressurized to about 145 psi. The valve was opened and the aerosolproduced was sampled into an Andersen Cascade impactor at a flow rate of28.3 l/min. The silicon anti-foam was allowed to dry by sampling clean,31% relative humidity air for 12 minutes. The Andersen was then used tosample ammonium fluorescein test aerosol produced as described inExample 7. The plates were analyzed, and a size distribution of theaerosol was plotted. The same ammonium fluorescein aerosol method wasused to sample into the Andersen impactor where the collection plateshad been coated with grease in the traditional manner, using a dropperto cover each plate with grease, and allowing them to dry overnight. Thesize distribution plot (FIG. 16) indicates that the two methods ofcoating the plates with grease produce nearly identical sampling resultsfor the test aerosol. Further, the aerosol method was suitable fordepositing a functional coating on each of the stages.

While preferred embodiments of the invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. Specific dimensionsgiven in the above examples are for the purposes of enablement of theexamples. It should be understood that various alternatives to theembodiments of the invention described herein may be employed inpracticing the invention, including alterations of the above statedspecific dimensions. While the examples presented have a specific numberof stages, it will be clear to one skilled in the art that additionalcollection stages may be similarly designed and added according to theteachings herein. It is intended that the following claims define thescope of the invention and that methods and structures within the scopeof these claims and their equivalents be covered thereby.

What is claimed is:
 1. A cascade impactor comprising: a series ofconcentrically-arranged collection stages and a terminating filter orfilter adapter stage, each of said collection stages comprising anelongated structure with a cylindrical shape, each of said elongatedstructures having a top end and a bottom end, the wall of each of saidelongated structures having an inner surface and an outer surface andfurther characterized by a single inner diameter, a first outerdiameter, and a second outer diameter, the top end of each of saidelongated structures being open and the bottom end of each of saidelongated structures being closed with a flat surface, each of saidelongated structures further comprising a region wherein the secondouter diameter is less than the first outer diameter to form anorifice-containing region on each of said elongated structures, the wallof each of said elongated structures further comprising at least oneorifice positioned in each of said orifice-containing regions andperpendicular to each of said walls and through which aerosol-containingair flows, wherein, for each of said elongated structures, the firstouter diameter is sized to fit within and slidably seal within the innerdiameter of the elongated structure of the next stage in the series, andwherein particles entrained in sampled air are collected on the innersurface of the wall of the stage opposite said respective at least oneorifice.
 2. The cascade impactor of claim 1 wherein said filter stage isfurther sized to receive the first outer diameter of the last collectionstage in said series.
 3. The cascade impactor of claim 1 wherein saidfilter stage is connected externally from the series of stages.
 4. Thecascade impactor of claim 1 designed to operate at a flow rate betweenabout 1 and about 15 lpm.
 5. The cascade impactor of claim 1 designed tooperate at a flow rate between about 1 and about 10 lpm.
 6. The cascadeimpactor of claim 1 designed to operate at a flow rate between about 2and about 8 lpm.
 7. The cascade impactor of claim 1 designed to operateat a flow rate between about 4 and about 6 lpm.
 8. The cascade impactorof claim 1 designed to separate particles with sizes between about 0.1and about 15 micrometers aerodynamic diameter.
 9. The cascade impactorof claim 1 designed to separate particles with sizes between about 0.3and about 12 micrometers aerodynamic diameter.
 10. The cascade impactorof claim 1 designed to separate particles with sizes between about 0.5and about 8 micrometers aerodynamic diameter.
 11. A cascade impactorcomprising a series of concentrically-arranged collection stages and aterminating filter or filter adapter stage, each of said collectionstages comprising an elongated structure with a cylindrical shape, eachof said elongated structures having a top end and a bottom end, the wallof each of said elongated structures having an inner surface and anouter surface and further characterized by a first inner diameter, asecond inner diameter, a first outer diameter and a second outerdiameter, the top end of each of said stages being open and the bottomend being closed with a flat surface, each of said elongated structuresfurther comprising a region wherein the second outer diameter is lessthan the first outer diameter to form an orifice-containing region, anda region wherein the first inner diameter is greater than the secondinner diameter forming a step feature, the wall of each of saidelongated structures further comprising one or more orifices positionedin said orifice-containing regions of said elongated structures andperpendicular to said walls of said elongated structures and throughwhich aerosol-containing air flows, the first outer diameter of each ofsaid elongated structures being sized to fit within and slidably sealwithin the first inner diameter of the elongated structure of the nextstage and rest upon the step feature of said next stage in the series,and wherein particles entrained in sampled air are collected on theinner surface of the wall of the stage opposite said respective one ormore orifices.
 12. The impactor of claim 11 wherein more than oneorifice is present in one or more of said orifice-containing regions ofsaid collection stages.
 13. The impactor of claim 12 wherein said morethan one orifices are spaced equidistant around the circumference of thewalls of the collection stages.
 14. The impactor of claim 11 wherein thefirst and second inner diameters are the same for the first stage. 15.The impactor of claim 11 wherein particles entrained in the sampled airare further recovered from the bottom of each collection stage in theseries.
 16. The impactor of claim 11 wherein said filter stage isfurther sized to receive the first outer diameter of the last collectionstage in said series.
 17. The impactor of claim 11 wherein said filterstage is connected externally from the series of collection stages. 18.The cascade impactor of claim 11 designed to operate at a flow ratebetween about 1 and about 15 lpm.
 19. The cascade impactor of claim 11designed to operate at a flow rate between about 1 and about 10 lpm. 20.The impactor of claim 11 designed to operate at a flow rate betweenabout 2 and about 8 lpm.
 21. The impactor of claim 11 designed tooperate at a flow rate between about 4 and about 6 lpm.
 22. The impactorof claim 11 designed to separate particles with sizes between about 0.1and about 15 micrometers aerodynamic diameter.
 23. The impactor of claim11 designed to separate particles with sizes between about 0.3 and about12 micrometers aerodynamic diameter.
 24. The impactor of claim 11designed to separate particles with sizes between about 0.5 and about 8micrometers aerodynamic diameter.
 25. The cascade impactor of claim 11wherein excess liquid aerosol is collected in the bottom of eachcollection stage.